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An Overview of Lymphatic Filariasis Lymphedema

An Overview of Lymphatic Filariasis Lymphedema

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Lymphology 50 (2017) 164-182

AN OVERVIEW OF LYMPHATIC

S. Rajasekaran, R. Anuradha, G. Manokaran, R. Bethunaickan

Department of Immunology (SR,RB) and International Center for Excellence in Research (RA) National Institute of Health, National Institute for Research in Tuberculosis, and Department of Plastic Surgery (GM), Apollo Hospitals, Chennai, India

ABSTRACT Details on infection, safety profile, and status in clinical practices are also reported. Filariasis is caused by thread-like worms and is classified according Keywords: lymphedema, clinical to their presence in the vertebrate host. management, , surgical The lymphatic group includes Wuchereria intervention in lymphatic filariasis bancrofti, malayi, and Brugia timori. lymphedema Lymphatic filariasis, a -borne disease, has been one of the most prevalent The term “lymphatic filariasis” comprises diseases in tropical and subtropical countries infection with three closely related nematode and is accompanied by a number of worms – , , pathological conditions. It is estimated that and Brugia timori. All three parasites are currently (after 13 years of the MDA transmitted by the bites of infective mosquitoes programme) there are an estimated 67.88 and have quite similar life cycles in humans million LF cases that include 36.45 million with the adult worms living in the afferent microfilaria carriers, 19.43 million hydrocele lymphatic vessels while their progeny, the cases, and 16.68 million lymphedema cases. microfilariae, circulate in the peripheral Adult filarial worms reside in the lymphatics blood and are available to infect mosquito and lymph nodes and induce changes that vectors when they feed. result in dilatation of lymphatics and Lymphatic filariasis (LF) is a neglected thickening of the lymphatic vessel walls. mosquito-borne . In 2014, Progressive lymphatic damage and pathology 73 countries were considered to be endemic, results from the summation of the effect of among which 18 countries were at the tissue alterations induced by both living and surveillance stage and 55 were continuing to nonliving adult parasites. In recent years, apply mass treatment (mass drug adminis- there has been rapid progress in filariasis tration, MDA) (1). Lymphatic filariasis research, which has provided new insights afflicts 68 million people in 73 countries, into the pathogenesis of filarial disease, including 17 million persons living with diagnosis, chemotherapy, the host-parasite chronic lymphedema. In India LF is endemic relationship, and the genomics of the parasite. in 255 districts of 16 states and 5 Union We examined the clinical manifestations of Territories (UTs) of the country. Presently the disease, diagnosis, treatment, immune about 630 million of people in these endemic responses, and management including review states/UTs are at-risk of LF (2-4). LF is of pharmaceutical agents against filariasis. responsible for 5.9 million disability adjusted 165 life years (DALYs) (5-7). These infections Clinical Manifestations also lead to increased mortality (8-11). In addition to the economic loss due to lost The clinical manifestations of LF are productivity, there are negative social and varied. Traditionally, it has been accepted cultural effects of the diseases (12). Elimina- that people living in an endemic area can tion of lymphatic filariasis is possible by be classified into five groups: [1] endemic interrupting the transmission cycle. normals; [2] clinically asymptomatic, Providing treatment on a large-scale to infected; [3] acute clinical disease; [4] chronic entire communities where the infection is pathology, and [5] tropical pulmonary present can stop the spread of infection. This eosinophilia. strategy of preventive chemotherapy, called mass drug administration (MDA), involves a Endemic normals combined dose of 2 drugs given annually to an entire at-risk population in the following In an endemic area, a proportion of the way: (400 mg) together with population remains uninfected despite ivermectin (150-200 mcg/kg) or with diethyl- exposure to the parasite. This group has been carbamazine citrate (DEC) (6 mg/kg). These termed as endemic normals. drugs have a limited effect on adult parasites but effectively reduce microfilariae from the Asymptomatic infection bloodstream and prevent the spread of microfilariae to mosquitoes (13). In areas endemic for lymphatic filariasis, many individuals exhibit no symptoms of Life Cycle of Lymphatic Filariasis filarial infection and yet, on routine blood examinations, demonstrate the presence of All human filarial have a significant numbers of parasites or the complex life cycle involving an insect vector, presence of circulating parasite antigen (a with Wuchereria and Brugia being trans- surrogate for viable adult worms). These mitted by mosquitoes. Infection begins with individuals are carriers of infection. With the deposition of infectious-stage larvae or the availability of better imaging techniques L3 larvae in the skin during a mosquito bite. (e.g., ultrasound, lymphoscintigraphy, MRI, The larvae then crawl in through the puncture CT), it has become apparent that almost wound and enter into the lymphatics and everyone with active infection (e.g., micro- lymph nodes. They undergo a process of filarial positivity) has some degree of molting and development to form L4 larvae lymphatic abnormality that may include: and then adult worms. The adult worms dilatation and tortuosity of lymph vessels reside within the lymphatics and lymph with collateralization, increased or abnormal nodes and following mating, release live patterns of lymph flow (14-16), urogenital progeny called microfilariae (mf), which lymphangiectasia (17-18), and microscopic circulate in the bloodstream. A mosquito can hematuria and/or proteinuria (19). At least then ingest these microfilariae during a blood half of all patients with lymphatic filariasis meal, wherein they undergo development appear clinically asymptomatic. This to form L2 and finally L3 larvae, and the asymptomatic presentation exists despite the life cycle continues. The complex life cycle presence of microfilariae in their blood and provokes a complicated host immune hidden damage to their lymphatics (20). response, and it is this complexity of the host-parasite interaction that is thought to Acute clinical disease underlie the varied clinical manifestations of lymphatic filariasis. Acute manifestations of lymphatic 166 filariasis are episodic attacks of lympha- trunks become very painful and the skin on denitis and lymphangitis (, pain in the the arms and legs may show red streaks from affected part, tender red streaks) along with the infected lymphatics. The distal end of the fever and malaise. Over 90% of cases with affected limb becomes swollen during the chronic manifestations will give a history of attack and remains swollen for several days. acute attacks. During acute infection, the Usually the swelling is initially limited to a microfilariae are transmitted by mosquitoes single limb. of various species. Occasionally the adult worms and their associated granulomatous Chronic pathology reaction are manifested as lumps in the subcutaneous tissue, breasts, or testicles (20- The chronic pathology of lymphatic 22). Acute filariasis is characterized by filariasis develops years after initial infection episodic occurrence of inflammation of the (26). The most commonly affected nodes are lymph glands (lymphadenitis), inflammation in the femoral and epitrochlear regions. of the lymph channels (lymphangitis), and Abscess formation may occur at the nodes or subsequent swelling of the limbs or scrotum anywhere along the distal vessel. Infection (lymphedema). Filariatic fever is often seen with Brugia timori (B. timori) appears to with headache and chills and will usually result in more abscesses than infection with occur at the same time as lymphangitis. B. malayi (27) or W. bancrofti (28). The Lymphadenitis and lymphangitis are charac- granulomas are characterized by macrophages teristic of both the W. bancrofti and B. malayi (which develop into giant cells), with plasma forms. The lymph nodes commonly involved cells, eosinophils, neutrophils, and lympho- are the inguinal, axillary, and epitrochlear cytes and with hyperplasia of the lymphatic nodes and the lymphatic system of the male endothelium, occuring with repeated genitals are frequently affected in W. bancrofti inflammatory episodes. The consequence is infection leading to funiculitis, epididymitis, lymphatic damage and chronic leakage of and/or orchitis (23). The funiculo- protein-rich lymph in the tissues, thickening epididymoorchitis, lymphadenitis and and verrucous changes of the skin, and retrograde lymphangitis, has been termed chronic bacterial and fungal infections, acute dermatotolymphangitis, a process which all contribute to the appearance of characterized by development of cutaneous or elephantiasis. B. malayi elephantiasis is more subcutaneous inflammation and accompanied likely to affect the upper and lower limbs, by ascending lymphangitis and regional with genital pathology and chyluria being lymphadenitis. This manifestation is thought rare. The current staging for filariasis-related to result primarily from bacterial and fungal lymphedema of the leg with defining superinfections of the affected limbs (24). symptoms is listed in Table 1. Lymphadenitis and lymphangitis are characteristic of both the W. bancrofti and Tropical pulmonary eosinophilia B. malayi forms (25). In lymphadenitis, the parasite essentially lodges inside the lymph Tropical pulmonary eosinophilia (TPE) nodes in the body, causing immune reaction is a distinct syndrome that develops in some and inflammation. Blockage and stretching individuals infected with W. bancrofti and of the lymph vessels by the adult worms B. malayi (29-30). Tropical pulmonary make it difficult for lymph to flow out of the eosinophilia is an extreme immune response lymphatics and back into the blood stream. to filarial infection. High eosinophilia levels, Inflammation of the lymph channels and asthma-like symptoms, and restrictive lung lymph nodes along with a decreased draining disease are characteristics of TPE. This efficiency leads to lymphedema. Lymphatic manifestation occurs with low frequency in 167

TABLE 1 Stages of Lymphedema of the Leg

endemic areas. Chest x-rays may be normal scintigraphy also revolutionized the diagnosis but generally show increased bronchovascular of the disease and may be very helpful in markings; diffuse miliary lesions or mottled monitoring the success of chemotherapy. In opacities may be present in the middle and TPE, serum antibodies like IgG & IgE will be lower lung fields. Total serum IgE levels extremely high and the presence of IgG4 (10,000 to 100,000 ng/mL) and antifilarial antibodies indicate active infection. A brief antibody titers are characteristically elevated. review and summary of these techniques are:

Diagnosis of Lymphatic Filariasis 1. New techniques for antigen detection represent the highest quality lab test for Diagnosis of LF was once an extremely diagnosing infection by W. bancrofti. PCR challenging task but with the advent of recent tests are also of high specificity and antigen-detection techniques, such as ICT sensitivity and detect parasite DNA in and FST card test and ELISA-based on the microfilariae in the blood of humans as well Og4C3 monoclonal antibody, diagnosis has as in vectors in both bancroftian and brugian become much easier. Molecular xenomoni- filariasis (31). Very high levels of specific toring (MX), which detects filarial DNA in IgG4 antibody in microfilaraemic patients mosquitoes by PCR, is a highly sensitive have also been considered as a good assay. Ultrasonography (USG) and lympho- diagnostic marker. 168

2. Immunochromatographic test (ICT) in the vicinity of adult worm nests (37-39). and Filaria Strip Test (FST), which are highly Subclinical lymphangiectasia of the lymphatic sensitive and specific filarial antigen detec- vessels containing live adult worms has been tion assays, are available for the diagnosis of shown to exhibit distention with no apparent W. bancrofti infection (31, 32). With these inflammatory reactions in the vessel wall, tests, the parasite antigens can be detected with little or only a fleeting inflammatory independent of the microfilariae’s periodicity. response to living adult parasites. Further, It is rapid (1-10 minutes), and no such test the fact that lymphangiectasia is not exists for Brugian filariasis. ELISA-based restricted to the exact segment of lymphatics assay using the Og4C3 monoclonal antibody where the worms reside (40) suggests that is equally sensitive and specific for detecting this process is mediated by soluble products antigen in bancroftian infections. excreted or secreted by the parasite that act on the lymphatic endothelial cells. It is also 3. Basic parasitologic testing of clear that with the advent of adaptive peripheral blood for microfilariae remains a immunity, the host inflammatory response diagnostic standby, keeping the periodicity against the dead or dying worm and the of the microfilariae in mind (31). subsequent release of parasite products and inflammatory mediators, a stage of irreversible 4. Ultrasonography using a 7.5 or 10 lymphatic dysfunction ensues (41-43). This MHz probe has helped to locate and visualize then manifests clinically as progressive the movements of living adult filarial worms lymphedema. In addition, lymphatic dysfunc- of W. bancrofti principally in the scrotal tion has been shown to predispose infected lymphatics of asymptomatic males with individuals to secondary bacterial and fungal microfilaraemia (33-36). infections and trigger inflammatory reactions in the skin and subcutaneous tissue that 5. Lymphoscintigraphy has been found accelerates the progression of lymphedema useful in tracing lymphatic damage and and precipitates the development of dermal backflow after injecting radiolabeled elephantiasis (44-45). proteins intradermally in both symptomatic Cells of the innate and adaptive immune and asymptomatic infections. system are important for the initiation of type 2 immunity, which are the hallmark of Pathogenesis of Filarial Disease helminth infections. The key players in T helper (Th) 2-type immunity are CD4+ Th2 The most severe clinical manifestations cells and involve the cytokines-IL-4, IL-5, of lymphatic filariasis are lymphedema and IL-9, IL-10, and IL-13; the antibody isotypes- elephantiasis. Although the immune responses IgG1, IgG4, and IgE, and expanded to filarial parasites have been well studied populations of eosinophils, basophils, mast with respect to natural history, diagnosis, and cells, and alternatively activated treatment, there is a relative paucity of macrophages (46-47). information in terms of the mechanisms The importance of pro-inflammatory underlying development of pathology. cytokines, possibly of innate origin, in the The two major independent components pathogenesis of lymphedema has been of lymphatic filarial disease are lymphangi- strengthened by a series of studies in humans ectasia and inflammatory reactions. While with chronic pathology, either in early or late most infected individuals exhibit lymphangi- stages or lymphedema. Studies have shown ectasia, clinically apparent lymphedema may that individuals with chronic lymphatic not be common. It is also clear that with pathology have elevated levels of C-reactive patent infection, lymphangiectasia develops protein (an acute phase protein, indicating an 169 acute inflammatory response) (48), pro- microbial products, acute-phase proteins, inflammatory cytokines such as TNF-α, and the so-called microbial translocation IL-6 and soluble TNF receptor (49-50), molecules (58,59). However, intra and peri- endothelin-1 and IL-2 (51), as well as IL-8, lymphatic damage – an underlying feature of MIP-1α, MIP-1β, MCP-1, TARC and IP-10 filarial disease – might also contribute to the (75) in the peripheral circulation. Similarly, presence of microbial translocation products while patients with both acute and chronic in the bloodstream. Indeed, the increased manifestations of LF have elevated circulating levels of LPS (which serves as a circulating levels of IL-6 and IL-8, only those marker for microbial translocation) and with chronic disease manifestations have decreased levels of LPS-binding protein elevated levels of sTNF receptors (52). (LBP) are characteristic features of filarial The endothelium appears to be closely lymphatic pathology that in turn appear to associated with pathogenesis of lymphatic cause immune activation. Since filarial disease and studies targeting the interaction lymphedema is known to be associated with between endothelial cells (blood vascular or increased bacterial and fungal loads in the lymphatic) and filarial parasites have been lymphatics, our studies reveal that these performed. Differentiation of LEC into tube- damaged lymphatics may serve as a potential like networks was found to be associated with nidus for bacterial translocation through significantly increased levels of matrix leaky lymphatic endothelium. metalloproteinases (MMPs) and inhibition of Multi-color flow cytometry analysis their endogenous inhibitors-TIMPs (tissue reveals that the frequency of Th1 cells inhibitors of MPs) (53). Recent data suggest (CD4+ T cells expressing either IFNγ or IL-2 that an increase in circulating levels of MMPs or TNF-α) (60), Th9 cells (CD4+ T cells and TIMPs is characteristic of the filarial expressing IL-9 and IL-10) (61), Th17 cells disease process and that altered ratios of (CD4+ T cells expressing IL-17) (62), and MMP/TIMP are an important underlying Th2 cells (CD4+ T cells expressing IL-22) is factor in the pathogenesis of tissue fibrosis in significantly enhanced in filarial pathology. filarial lymphatic disease. Other studies have This is accompanied by a concomitant implicated the vascular endothelial growth decrease in the frequency of Th2 cells (CD4+ factor (VEGF) family in lymphangiogenesis T cells expressing IL-4 or IL-5 or IL-13) both (54-56). Other angiogenic factors such as at homeostasis and following parasite antigen angiopoietins-1 and -2 are also found at stimulation (63). Although less well studied elevated levels in individuals with filarial- than Th1 cells, Th17 cells might also have induced pathology (57). A major factor an important role in the pathogenesis of involved in the initiation of the proinflam- disease in filarial infection since PBMC from matory response and the increased produc- individuals with pathology (but not asympto- tion of VEGF-A and -C might be the matic patients) express significantly higher endosymbiont, , present in most levels of the Th17 associated cytokines as well filarial nematodes (including W. bancrofti as the master transcription factor – RORC and the 2 Brugia spp) (55). Recently, it has at the mRNA level. been demonstrated that the increased levels Finally, pathology in lymphatic filariasis of VEGF-C and sVEGF-R3 (observed in is also associated with expanded frequencies lymphedema patients) were reduced of Th9 cells, CD4+ T cells that express following doxycycline treatment (a regimen both IL-9 and IL-10 but not IL-4, and this that eliminates Wolbachia) and that there frequency exhibits a positive correlation was improvement in lymphedema (56). with the severity of lymphedema in filarial Persistent immune activation is infections. associated with elevations of circulating 170

Wolbachia and its Role 73 endemic countries have morbidity programs. During 2000-2012, the MDA Wolbachia of filarial nematodes are the programme made remarkable achievements – obligate intracellular alpha-proteobacteria a total of 6.37 billion treatments were offered and have some resemblances with insect and an estimated 4.45 billion treatments Wolbachia. Wolbachia bacteria are vertically were consumed by the population living in transmitted to the filarial progeny through endemic areas. Using a model based on the female germline (64). From the entry of empirical observations of the effects of the parasite to the establishment of the treatment on clinical manifestations, it is chronic disease, Wolbachia plays multiple estimated that 96.71 million LF cases, roles, such as exacerbating proinflammatory including 79.20 million microfilaria carriers, pathogenesis and immunomodulation of the 18.73 million hydrocele cases and a minimum host, as well as enhancing survival of the of 5.49 million lymphedema cases have filariae. Wolbachia can trigger a proinflam- been prevented or cured during this period. matory response through interaction with Consequently, the global prevalence of LF monocytes/macrophages, dendritic cells, is calculated to have fallen by 59%, from and neutrophils (65-66). Anti-Wolbachia 3.55% to 1.47%. The fall was highest for therapy with doxycycline (a semisynthetic microfilaraemia prevalence (68%), followed derivative of the tetracycline family) has by 49% in hydrocele prevalence and 25% in been recommended for the treatment of lymphedema prevalence. These programs individuals with lymphatic filariasis (67-68). focus on hygiene, skin care, hydrocele It allows the development of filariae in their surgery, and exercises. The GPELF plan for vector to be blocked, thus arresting the 2010-2020 highlights the need for the transmission. Wolbachia thus prevents the establishment of morbidity management degranulation of eosinophils by triggering an programs in all endemic regions. In ineffective neutrophil response by the host particular, the plan identifies the need for (69). Wolbachia is being revealed as an the development of metrics to monitor and important cause of pathology in filarial report on the outcomes of these programs. diseases. Symptoms are correlated with The National Filaria Control Programme increases in the levels of circulating (NFCP) was launched in India in 1955. The Wolbachia protein and DNA, and with the control strategy was selective chemotherapy detection of antibodies directed against the with citrate (DEC) for endosymbiont (70-72). 12 days at 6 mg/kg body weight for parasite carriers detected from the night blood survey, Elimination Program and Treatment and larval control of vector mosquitoes. The major constraint of the NFCP was that it did The Global Program to Eliminate not cover the vast majority of the population Lymphatic Filariasis (GPELF) recently at risk residing in rural areas and that the released their progress report for 2014. strategy demanded detection of parasite The report summarized the work of the carriers by night blood survey, which is less GPELF’s first decade, which was focused sensitive, expensive, time-consuming and on implementing mass drug administration poorly accepted by the community (73). (MDA) across all LF endemic regions. The report acknowledged that while MDA Vector control programmes have been particularly successful in reducing infection within communities, Vector-control strategies in the last efforts to reduce morbidity associated with century were based on chemical agents and LF remain lacking. Currently, only 24 of the current ecological and environmental 171 protection standards largely no longer reduction in limb volume was reported in support such approaches due to adverse lymphedema, greater benefits were effects of many insecticides on non-target experienced among participants with early species (including humans), their environ- stages, suggesting that implementation of a mental impact, contamination of soil and self-care routine as soon as lymphedema is water, and development of selective processes detected has the potential to curtail the and subsequent mosquito resistance to number of cases that progress to advanced insecticides (74). New strategies therefore stages. Bernhard et al reported that limb had to be created to replace the use of volume reduction was significantly greater insecticides. Genetic control methods have in the self-treating group compared to the now arisen as promising alternative strategies, therapist treated group. Douglass et al’s based on two approaches: the replacement review supported the adoption of remedial of a vector population by disease-refractory exercises in the management of lymphedema mosquitoes, and the release of mosquitoes and a greater emphasis on self-treatment carrying a lethal gene to suppress target practices for people with lymphedema (105). populations. Genetically modified bacteria To eliminate lymphatic filariasis, the capable of colonizing a wide range of Indian Government has launched a mosquito species may be a solution to this substantial public health initiative in which problem and another option for the control of they provide free prophylactic drugs to more these diseases. In the paratransgenic approach, than 400 million people in the country. The symbiotic bacteria are genetically modified initiative includes providing an annual dose and reintroduced in mosquitoes, where they of preventive drugs (diethylcarbamazine and express effector molecules. In this approach, albendazole) to entire communities in the a genetic modified bacteria can act by: form of mass drug administration. To (a) causing pathogenic effects in the host; support this initiative, India’s Ministry of (b) interfering with the host’s reproduction; Health and Family Welfare in collaboration (c) reducing the vector’s competence; and with the Global Network for Neglected (d) interfering with oogenesis and Tropical Diseases (an initiative of the embryogenesis (75-76). Washington-based Sabin Vaccine Institute) has launched a public service advertising Self-help groups or social helping groups campaign called Hathipaon Mukt Bharat (Filaria Free India). The campaign includes Effective self-care implementation a film entitled Giant footprints! in which a requires some degree of education, instruction patient with lymphatic filariasis is shown or demonstration, and the role of the delivering the message that the disease “can educated health worker or trained volunteer happen to anyone,” that people should cannot be ignored. Studies which provided participate in the mass drug administration frequent monitoring and support were initiative, and that they should take the associated with greater improvements than preventive medicines (which are free and studies which offered minimal or no support safe) to make India filaria free. The campaign services. Study by Akogun and Badaki (77) supports the Indian government’s mass where one group was able to alter the program drug administration initiative, which is being design to suit their immediate cultural and implemented in 17 states (82). social constraints reported good outcomes. A study by Wilson et al and others (78-81) Tools for assessment of elimination reported that basic self-care improved skin integrity and prevented new infections while Lymphatic filariasis is targeted for limb stage remained the same. Where a global elimination through treatment of entire 172 at-risk populations with repeated annual considerable economic loss and deterioration mass drug administration (MDA). Essential of quality of life. Prompt treatment and for program success is defining and prevention of ADL are of paramount impor- confirming the appropriate endpoint for tance. ADL may be seen both in early and MDA when transmission is presumed to late stages of the disease. It is due to the have reached a level low enough that it infection and inflammation of the skin and cannot be sustained even in the absence of affected area from entry of bacteria or fungus drug intervention. Guidelines advanced by through the entry lesions. The skin becomes WHO call for a transmission assessment warm, tender, painful, swollen, and red, and survey (TAS) to determine if MDA can be the patients can develop fever, headache, stopped within an LF evaluation unit (EU) chills, and sometimes nausea and vomiting. after at least five effective rounds of annual They can also occasionally become septicemic. treatment. The decision to stop MDA is The first sign will be enlarged, tender, and complicated and a variety of tools have been painful swollen lymph nodes which lasts for suggested to guide the decision. The first step 4-5 days. Peeling and darkening of skin is is to define the parameter(s) that will be common and repeated attacks increase the measured and the best diagnostic tool for size of the legs. Management includes assessing it. At least eight diagnostic tests are symptomatic treatment like relieving pain, currently available for detecting indicators antibiotics to combat bacterial infection, care of LF exposure and infection. These include of entry lesions, etc. In patients with late Bm14, PanLF, Wb123, Urine SXP, ICT, stages of lymphedema, long term antibiotic Og4C3, Blood smear, and PCR therapy using oral Penicillin or long acting parentral Benzathil Penicillin are sometimes Therapy for Lymphatic Filariasis used to prevent ADL.

Remarkable advances in the treatment Surgical treatment of LF have recently been achieved focusing not on individuals but on communities In the surgical aspect of lymphatic with infection. The overall goal is to reduce filariasis, grade I and grade II can be treated mf in the community to levels below which conservatively, whereas grade III and grade successful transmission will not occur. IV needs surgical correction together with regular antibiotics and chemotherapy with Drugs effective against filarial parasites DEC. The old surgical techniques of excision 1. Diethylcarbamazine citrate (DEC) and skin grafting are no longer practiced as 2. DEC-Fortified salt it gives poor cosmetic results along with early 3. Ivermectin recurrences. Thompson’s, Kondolean, and 4. Albendazole Charles procedures are no longer utilized 5. Levamisole hydrochloride and newer techniques involving micro- 6. Moxidectin vascular surgery like nodovenal shunt and Treatment of microfilaraemic patients lymphovenal shunt with reduction and may prevent transmission of infection and sculpturing is being carried out without skin may be repeated every 6 months till mf grafting or a flap cover. Patient’s local skin and/or symptoms disappears. itself has been salvaged and made to a better quality by manual lymph drainage (MLD), Treatment and prevention of ADL bandaging, and use of the same skin for reconstitution (83). The most distressing aspect of LF is The future of lymphedema surgery the acute attacks of ADL, which result in will be supermicrovascular surgery with 173 lymphatico-venous anastomosis at multiple standard form of treatment and this can be levels or a free microvascular lymph node done using different surgical techniques. The transfer to the affected areas. The anastomosis prevalence of chronic hydrocele in bancroftian can be performed either by glue or by laser. filariasis endemic areas-a But our idea is to focus on prevention of transmitted by mosquito-is very high and lymphatic filariasis and elimination in future, represents the most common clinical manifes- which does not warrant any new surgical tation of bancroftosis followed by swollen technique. We are concentrating on earlier legs of lower limbs or lymphedema among detection of problems and creating awareness women. The surgeons’ preference is for among the people and general precautions so surgical techniques in which the hydrocele that the infected people can be treated at an sac is opened, averted with or without partial earlier reversible stage. resection of the sac, and the edges sutured behind the testis. To avoid hydrocele Scrotal surgery recurrence, earlier recommendation was to a complete excision of hydrocele sac and when Lymph scrotum almost always occurs in identified, leaking or leak-prone dilated patients with a previous history of acute lymphatic vessels should be sutured or excised. episodes of filariasis that are characterized by By surgical practice, a simple reduction lymphangitis due to bacterial and/or fungal of scrotum and excision of penile skin with infection and who present chronic lymphan- skin grafting has been done. Unfortunately, giectasia. Lymph scrotum or superficial as there was no continuous drainage, these scrotal lymphangiomatosis is a urogenital patients develop recurrences. Hence we came condition characterized by the presence of out with a new strategy of reducing the lymphatic vesicles on the surface of the scrotum by doing hydrocelectomy, together scrotal skin that can easily rupture giving with the excision of penile edematous skin rise to drainage of the whitish fluid typical of and resurfacing of penis using the prepusal the disease (84-88). This fluid serves as an layer of the penis itself, followed by a excellent culturing medium that favors bilateral nodo-venal shunt. The advantage of repeated bacterial infections. It may trigger using this procedure is to avoid recurrence, progression of the condition to lymphedema retain the shape and sensation of the penis, and scrotal elephantiasis, the advanced stages and provide a more acceptable, functional, of the disease. Lymph scrotum is a less and aesthetic result for the genital region as frequent manifestation of LF, however it has it has been a neglected and important focus important medical, psychological and for the patients. socioeconomic repercussions for individuals who present this condition as it is seen as the Herbal treatments/yoga/traditional healing complication of LF that produces the greatest incapacitation among men (88). There are several herbs that have been prescribed by Ayurveda for the treatment Hydrocelectomy of elephantiasis for centuries. The following are some of the herbs reported as having Chronic hydrocele is the accumulation antifilarial activities i.e., Vitex negundo L. of fluid around the testis leading to an (roots), Butea monosperma L. (roots and increase in the volume of the scrotal contents. leaves), Ricinus communis L. (leaves), Aegle Depending on the volume of fluid, hydrocele marmelos Corr. (leaves) (89), Canthium can be disfiguring and even incapacitating. mannii (Rubiaceae) (90), Boerhaavia diffusa Chronic hydrocele has multiple etiologies, L. (whole plant) (91). Two compounds, but irrespective of the cause, surgery is the oleanonic acid and oleanolic acid, isolated 174 from hexane and chloroform fractions in vitro complete cure, but the “foot care programme” killed adult B. malayi (92). Calotropis procera may offer relief, some amelioration, and R. Br. leaves was used as traditional home prevention of acute attacks and thus limitation remedy to reduce pain and swelling during of further progression of the swelling. inflammatory episodes (93). Narahari et al (94) developed a treatment Current control strategy of LF protocol for lymphedema integrating ayurveda, biomedicine, and yoga. Yoga used In view of achieving the global elimina- as a major component of integrative tion of LF, the program in India has been treatment protocol in 14 Indian village camps made a part of the NVBDCP in 2003, under improved quality-of-life in 425 lymphatic the National Health Policy 2002, and set a filariasis patients. Long standing lymphedema target for elimination of LF by 2015. The caused altered gait and joint deformities in strategy for achieving this goal was initially small and large volume limbs. This was by annual MDA single dose DEC (6 mg/kg mostly due to the inactivity causing muscle body wt.) for at least five years to the entire weakness and edema within and around the population of an endemic district (excluding muscles. Yoga postures improve movements children under two years, pregnant women and helped the patients to negotiate with and severely ill patients), and home-based these deformities (95). Narahari et al management of lymphedema cases and showed that the lymph drainage achieved in hydrocelectomy operations in identified these patients was plausible because of Community Health Centres (CHCs) and breathing, movements coordinated with hospitals. breathing, and stimulation of autonomic MDA with DEC was launched as a pilot system. There is no evidence that breathing project in 13 districts of seven states in the facilitates the lymphatic drainage in much year 1996 (97). The NVBDCP upscaled the dilated human truncal lymphatics. Their MDA to cover a population of 77 million in study included a total of 730 patients (851 2002 from 41 million in1996-97. During the limbs) from two LF endemic districts of south year 2004, a population of about 468 million India -Gulbarga in Karnataka and Alleppey from 202 districts was targeted for MDA. in Kerala- and all patients were given There have been several reviews of the use training in the integrative procedure which of Albendazole (Alb) for MDA towards the involved patient education and the elimination of LF (98-102). A large-scale domiciliary protocol. At completion of the trial on the feasibility and impact of co- three and half month follow up, there was a administration of DEC and Alb in selected statistically significant reduction up to mid- districts in the country was carried out in thigh level volume measurement for both 2000-05, with the support of Indian Council small and large limbs. Yoga offers a self-care of Medical Research (ICMR) Task Force. It management tool for lymphedema albeit therefore recommended the co-administration there is lack of evidence that breathing (DEC 6 mg/kg/ body wt. and Alb 400 mg) actually achieves lymphatic drainage (96). strategy for all endemic districts in India. A new trial using triple drug therapy (DEC+ Treatment and Prevention of Lymphedema Albendazole+ Ivermectin) has started in and Elephantiasis Karnataka and is being conducted by VCRC to evaluate the efficacy of triple drug therapy Early treatment with drugs may destroy annually compared to DEC+ Albendazole the adult worms and logically prevent the annually. If effective, the national programme later development of lymphedema. Once might implement triple drug therapy for MDA lymphedema is established there is often no for the remaining endemic areas in India. 175

Disease Management that can hardly be seen which may cause itching. Scratching can further damage the Filarial patients with skin lesions often skin and can provoke an acute attack. have more bacteria on the skin than usual. Toenails should be trimmed in such a way The large number of bacteria on the skin, that the skin is not injured. Do not try to multiple skin lesions, slow lymph fluid move- clean under the nails with sharp objects as ment from the damaged lymphatics, and the these can cause entry lesions. It is important reduced ability of lymph nodes to filter the to check the skin every time the leg is washed bacteria cause inflammation characteristic of because entry lesions allow bacteria to enter an acute attack. Repeated bacterial infections the skin and this will cause acute attacks. precipitate frequent acute attacks, which If entry lesions are found, they should be further damage lymphatic vessels in the skin, cleaned carefully. reducing their ability to drain fluid. This Washing the leg includes: (i) Wet the leg vicious cycle continues, aggravating the with clean water at room temperature. Do condition of the patient. not use hot water to wash the leg; (ii) Begin Lymphedema management involves the soaping at the highest point of swelling following components: washing, prevention (usually around the knee); (iii) Wash down and cure of entry lesions, elevation of the the leg towards the foot; (iv) Gently clean foot, exercise, wearing proper footwear, and between all skin folds and between the toes, management of acute attacks. preferably using a small cloth or cotton swab, The GPELF aims to provide access to a and paying particular attention to the entry minimum package of care for every person lesions. Brushes should not be used as they with associated chronic manifestations of can damage the skin; (v) Rinse with clean lymphatic filariasis in all areas where the water; (vi) Repeat this careful washing until disease is present, thus alleviating suffering the rinse water is clean; (vii) Wash the other and promoting improvement in their quality leg in the same way, even if it looks normal. of life. Success in 2020 will be achieved if Drying the skin includes: (i) Patting the patients have access to the following area lightly with a clean towel. Do not rub minimum package of care: treatment for hard because this can cause damage to the episodes of adenolymphangitis (ADL); skin; (ii) carefully dry between the toes and guidance in applying simple measures to between skin folds using a small cloth, gauze manage lymphedema and hydrocele to or cotton swab. Wet areas between the toes, prevent progression of lymphedema and skin folds and entry lesions promote bacterial debilitating, inflammatory episodes of ADL; and fungal growth leading to frequent acute surgery for hydrocele; treatment with anti- attacks. filarial medicines to destroy any remaining worms and microfilariae by preventive Prevention and cure of entry lesions chemotherapy or individual treatment; and doxycycline for early stage lymphedema. Entry lesions are common in patients with lymphedema and are most frequently Washing and skin care found between the toes and deep skin folds and around the toenails. Entry lesions, such Good hygiene and treatment of entry as wounds, can also be found on the surface lesions are important measures for managing of the skin. Both fungi and bacteria can cause lymphedema. The patients should be entry lesions. Fungal infections frequently encouraged to practice skin care and hygiene. damage the skin and create entry lesions, The skin must be checked for entry lesions, especially between the toes, and may cause including very small lesions between the toes itching. The entry lesions allow bacteria to 176 enter the body through the skin and this can on regular washing, careful drying, and treat- cause acute attacks. Fungi and bacteria can ment, with antifungal, antibiotic, or emollient cause bad odor. creams, of the affected limbs, limb elevation, exercise, and use of footwear) has not yet Fungal infections reached all study communities and the local physicians are not aware of them (103-105). Fungal infections are usually white or pink in color and do not leak fluid. Bacterial Wearing proper footwear infections may leak fluid that is thin and clear or thick and colored. Antifungal and Proper footwear protects feet from injury antibacterial creams can be used for local and counseling the patients is important. application. Management of acute attacks Elevation The reduction in the frequency of the Elevation is important for patients with acute attacks is an indication that the lymphedema of the leg. It helps prevent fluid patient’s condition is improving. An acute from accumulating in the leg by improving attack is painful. The patient may complain the flow in the elevated position. The knee of fever, nausea, headache, and soreness of should be slightly bent and a pillow placed the lymph nodes. Most patients can easily under the knee for support. While sitting, care for their acute attack. The patient raise the foot as high as is comfortable, should rest and elevate the leg comfortably preferably as high as the hip. If sitting on as much as possible at home. the floor, place a small pillow under the The following simple procedures can knees. If lying down, the foot can be raised alleviate the symptoms: (1) A cloth soaked in by placing a pillow under the mattress. water and placed around the leg can relieve pain. The leg can also be soaked in bucket Exercise of cold water; (2) The leg should be washed with soap and clean water, but gently and Exercise is useful for patients with carefully; (3) After drying, antiseptic can be lymphedema and in general, the more they applied to the skin and medicated cream; exercise the better they are. Exercise helps by (4) The patient should drink plenty of water; pumping the fluid and improving drainage. (5) Paracetamol can be taken for fever every However, patients should not exercise during six hours until the fever lessens; and (6) Oral acute attacks. antibiotics which can shorten the attack are Walking short distances and standing up recommended. on toes exercise is a common approach. Patients can stand with both feet slightly CONCLUSION apart, holding on to a wall, a person, or other support and then raise on to the toes of both In this review we have focused on the feet at the same time and then sink back epidemiology of LF, clinical manifestations, down to flat feet. While sitting or lying down, pathogenesis of LF and immune response, they can point toes towards the floor, then current strategy for clinical management, bend (extend) the toes upwards, and finally and disease management. The creation of move the foot in a circle to the right and left. GAELF has shown that it is possible to bring If patients are sitting on the floor, it is good different organizations and donations to protect the heel with a flat pillow. Modern together under one umbrella to coordinate lymphedema management strategies (based and streamline global activities aiming at 177 eliminating LF transmission by 2020. In the that people living in an endemic area can endemic countries, progress has mostly been be classified into five groups: (1) endemic satisfactory, leading to lower numbers of normals; (2) clinically asymptomatic, infected people and to interrupted trans- infected; (3) acute clinical disease; (4) chronic mission. Mosquito control is a supplemental pathology and (5) tropical pulmonary strategy supported by WHO. It is used to eosinophilia (TPE) reduce transmission of lymphatic filariasis • While filarial infection does induce and other mosquito- borne infections. expression of immune cells in humans, early Depending on the parasite-vector species, interaction of parasites or parasite antigens measures such as insecticide-treated nets, leads to a predominantly pro-inflammatory indoor residual spraying or personal response with expression of mainly pro- protection measures may help protect people inflammatory cytokines including TNFα, from infection. Vector control has in select IL-6 and IL-1β, as well as genes involved in settings contributed to the elimination of inflammation and adhesion. lymphatic filariasis in the absence of large- • Increase in circulating levels of MMPs scale preventive chemotherapy. and TIMPs is characteristic of the filarial disease process and altered ratios of Key Points MMP/TIMP are an important underlying factor in the pathogenesis of tissue fibrosis • Lymphatic filariasis is a neglected in filarial lymphatic disease. mosquito-borne tropical disease which is • Elevated levels of VEGF-A, VEGF-C, caused by filarial worms, Wuchereria and endothelin-1 have been observed in the bancrofti, Brugia malayi, or B. timori. It is serum of filarial-infected individuals. endemic in 58 countries, putting 1.2 billion • Multi-color flow cytometry has shown people at risk globally with an estimated that the frequency of Th1 cells (CD4+ T cells 120 million infected. expressing either IFNγ or IL-2 or TNF-α); • Filariasis causes relatively low mortality Th9 cells (CD4+ T cells expressing IL-9 and but has a high incidence of morbidity IL-10); Th17 cells (CD4+ T cells expressing that has a major social impact causing heavy IL-17) and Th2 cells (CD4+ T cells expressing economic loss in developing countries. IL-22) is significantly enhanced in filarial • It is the second leading cause of pathology. permanent or long-term disability with over • Chronic pathology in lymphatic filariasis 40 million infected people suffering from is also associated with expanded frequencies pathological manifestations like lymphedema, of Th9 cells, CD4+ T cells that express both hydrocoele, chyluria, and elephantiasis IL-9 and IL-10. • The standard method for diagnosing •A basic, recommended package of care active infection is by finding the microfilariae can alleviate suffering and prevent further via microscopic examination. This may be disability among lymphatic filariasis patients. difficult, as in most parts of the world • Treatments for lymphatic filariasis differ microfilariae only circulate in the blood at depending on the geographic location of the night. For this reason, blood has to be endemic area (i.e., in some areas of the world, collected nocturnally. The blood should be in albendazole is used with diethylcarbamazine). the form of a thick smear and stained with Geo-targeting treatments is part of a larger Giemsa. Testing the blood for filarial antigen strategy to eventually eliminate lymphatic has been transformative in enabling the rapid filariasis by 2020. and accurate diagnosis of LF. • Lymphatic filariasis can be eliminated • The clinical manifestations of LF are by stopping the spread of infection through varied, Traditionally, it has been accepted preventive chemotherapy with single doses of 178

2 medicines for persons living in areas where All authors declare that no competing the infection is present. financial interests exist.

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